Rifamycin

Rifamycin belongs to the pharmacological class of Rifamycin derivatives. 

Rifamycin has been approved to relieve symptoms and also for the treatment and maintenance of Travelers' Diarrhea

After the administration of a 250 mg dose of rifamycin, the following pharmacokinetic parameters were reported: a peak concentration (Cmax) of 36 mg/L, reached within 5 minutes (Tmax), an area under the concentration-time curve (AUC) of 11.84 mg.h/L, and a mean residence time of 0.49 hours. The volume of distribution for rifamycin, measured after the same dosage, was found to be approximately 101.8 L. Rifamycin exhibits a protein binding capacity of around 80-95%. Metabolically, it is primarily converted to a 25-deacetyl metabolite in hepatocytes and intestinal microsomes following absorption. In terms of elimination, approximately 18% of the administered dose is recovered in feces within 24 hours, with the percentages increasing to 50% and 21% within 48 and 72 hours, respectively. Fecal elimination accounts for the majority (around 90%) of the administered dose, while urinary excretion plays a negligible role.

The common side effects involved in using Rifamycin are Headache, Constipation, Abdominal pain, Fever, Indigestion

Rifamycin is available in the form of Oral tablets, Oral suspension.

Rifamycin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Rifamycin belongs to the pharmacological class of Rifamycin derivatives. 

Rifamycins, along with other drugs in the same category, exert their antibacterial effects by inhibiting the synthesis of RNA. This mechanism involves strong binding to the DNA-dependent RNA polymerase found in prokaryotes. The inhibition of RNA synthesis is believed to primarily affect the initiation phase of the process and relies on stacking interactions between the naphthalene ring and the polymerase's aromatic component. Additionally, the presence of zinc atoms in the polymerase is thought to facilitate the binding of phenolic -OH groups from the naphthalene ring.

Rifamycin has been approved to relieve symptoms and also for the treatment and maintenance of Travelers' Diarrhea

After administering a 250 mg dosage of rifamycin, the observed maximum plasma concentration (Cmax) was reported to be 36 mg/L, the time to reach maximum concentration (Tmax) was 5 minutes, the area under the concentration-time curve (AUC) was 11.84 mg.h/L, and the mean residence time was 0.49 hours.

Rifamycin is found to be available in the form of Oral tablets, Oral suspension.

Rifamycin can be used in the following treatment:

• Travelers' Diarrhea

Rifamycin can help to relieve symptoms and also for the treatment and maintenance of Travelers' Diarrhea.

Rifamycin is approved for use in the following clinical indications:

• Travelers' Diarrhea

• Dosage for Travelers' Diarrhea:

For the treatment of Travelers' diarrhea, it is recommended to take 388 mg orally twice a day for a duration of three days.

Oral Tablets: Rifamycin tablets are designed for oral administration. They come in different strengths, typically ranging from 200 mg to 550 mg. The tablets are intended to be swallowed whole with water.

Oral Suspension: Rifamycin oral suspension is a liquid formulation that is taken orally. It is available in various strengths, usually ranging from 100 mg/5 mL to 200 mg/5 mL. The suspension should be shaken well before use and measured with a suitable dosing device.

Oral tablets, Oral suspension.

Rifamycin does not have specific dietary restrictions. However, it is generally recommended to follow a balanced and healthy diet while undergoing treatment with Rifamycin. It is important to maintain adequate hydration by drinking plenty of fluids.

Rifamycin may be contraindicated under the following conditions:

• Rifamycin is contraindicated in patients who have demonstrated hypersensitivity to the drug.

Risk Of Persistent Or Worsening Of Diarrhea Complicated By Fever And/Or Bloody Stool:

Rifamycin 's effectiveness in patients with diarrhea complicated by fever and/or bloody stool has not been demonstrated. Patients with these conditions who were treated with Rifamycin experienced a prolonged time to last unformed stool (TLUS). The medication's effectiveness in travelers' diarrhea caused by pathogens other than E. coli has also not been established. Consequently, Rifamycin is not recommended for use in patients with diarrhea accompanied by fever or bloody stools or caused by pathogens other than noninvasive strains of E. coli. If diarrhea worsens or persists for more than 48 hours, Rifamycin should be discontinued, and alternative antibacterial therapy should be considered.

Clostridium Difficile-Associated Diarrhea:

The use of nearly all antibacterial agents, including Rifamycin , has been associated with Clostridium difficile-associated diarrhea (CDAD), which can range in severity from mild diarrhea to fatal colitis. Administration of antibacterial agents alters the normal flora of the colon, leading to an overgrowth of C. difficile. CDAD occurs due to the production of toxins A and B by C. difficile. Hypertoxin-producing strains of C. difficile can cause severe infections that may be resistant to antimicrobial therapy and require colectomy. It is important to consider CDAD in all patients presenting with diarrhea after using antibacterial drugs. A careful medical history is necessary as CDAD cases have been reported up to two months after antibacterial administration. If CDAD is suspected or confirmed, discontinuation of antibacterial drugs not targeted against C. difficile may be necessary. Appropriate management, including fluid and electrolyte balance, protein supplementation, specific antibacterial treatment for C. difficile, and possible surgical evaluation, should be implemented based on clinical indications.

Development Of Drug-Resistant Bacteria:

Prescribing Rifamycin without a confirmed or strongly suspected bacterial infection or prophylactic indication is unlikely to provide any benefit to the patient and increases the risk of developing drug-resistant bacteria.

Nonclinical Toxicology:

Carcinogenesis, Mutagenesis, Impairment Of Fertility:

Carcinogenicity studies have not been conducted in animals with rifamycin, the active ingredient in Rifamycin .

Rifamycin has shown no genotoxic effects in bacterial reverse mutation assays, mouse lymphoma cell mutation assays, or mouse bone marrow micronucleus assays.

Fertility studies in animals with rifamycin have not been conducted.

• It is generally advised to avoid consuming alcohol while taking rifamycin. Alcohol may interact with rifamycin and potentially increase the risk of certain side effects or interfere with the effectiveness of the medication.
• Drinking alcohol while on rifamycin may lead to an increased risk of liver toxicity or liver damage. Rifamycin itself can already have an impact on liver function, and alcohol consumption can further strain the liver. Combining the two can potentially worsen liver-related side effects.
• To ensure the safe and effective use of rifamycin, it is recommended to abstain from alcohol during the course of treatment.

Information regarding the presence of Rifamycin in human milk, its effects on the breastfed infant, or its impact on milk production is currently unavailable. However, based on clinical pharmacology data, the systemic absorption of Rifamycin in humans is minimal after oral administration of the recommended dose. As a result, the exposure of a breastfed infant to Rifamycin through breast milk is expected to be insignificant. Animal lactation data following oral rifamycin administration is not available, but studies in lactating ewes have shown the passage of rifamycin into milk after intravenous injection. When considering the use of Rifamycin , it is important to weigh the developmental and health benefits of breastfeeding against the mother's clinical need for the medication and any potential adverse effects it may have on the breastfed infant, either from Rifamycin itself or the underlying maternal condition.

Pregnancy:

Teratogenic Effects - Category A

Data regarding the use of Rifamycin in pregnant women are not available, and therefore, the risks of major birth defects, miscarriage, or adverse outcomes for both the mother and the fetus are unknown. When Rifamycin is taken orally at the recommended dose, the systemic absorption in humans is minimal, indicating that fetal exposure to the drug is not expected. Animal studies conducted with Rifamycin showed no malformations in pregnant rats or rabbits at exposures 25,000 and 500 times higher, respectively than the human exposure achieved with the recommended clinical dose. However, when pregnant rats were treated with Rifamycin at more than 1,000 times the maximum plasma concentration and 25,000 times the systemic exposure during organogenesis, maternal toxicity, decreased fetal weight, and variations in diaphragm formation were observed. Similarly, pregnant rabbits treated with Rifamycin at more than 10 times the maximum human plasma concentration experienced maternal toxicity, decreased fetal weight, and slightly delayed fetal ossifications. It's important to note that all pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. Pregnant women should be informed about the potential risk to the fetus. In animal studies, higher doses of rifamycin did not cause malformations, but they did result in maternal toxicity and fetal developmental effects, while lower doses did not show adverse effects on fetal development in rats and rabbits.

There are no specific food warnings associated with the use of rifamycin. However, it is generally recommended to take rifamycin on an empty stomach at least 1 hour before or 2 hours after a meal. This is to ensure optimal absorption of the medication. Taking rifamycin with food, especially fatty meals, may decrease its absorption and effectiveness.

The adverse reactions related to Rifamycin can be categorized as follows:

Common:

• Headache
• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Flatulence (excessive gas)
• Rash or itching
• Dizziness
• Fatigue or weakness

Less common:

• Allergic reactions (such as hives, swelling, or difficulty breathing)
• Elevated liver enzymes
• Jaundice (yellowing of the skin or eyes)
• Dark-colored urine
• Pale stools
• Loss of appetite
• Muscle or joint pain
• Changes in taste sensation
• Insomnia or sleep disturbances

Rare:

• Severe allergic reactions
• Serious liver problems (such as hepatitis)
• Severe skin reactions (including Stevens-Johnson syndrome or toxic epidermal necrolysis)
• Blood disorders (such as decreased platelet count or hemolytic anemia)
• Kidney problems
• Neurological effects (such as confusion or hallucinations)
• Respiratory difficulties

• No clinical drug-drug interaction studies have been conducted for rifamycin (Rifamycin ).
• In vitro transporter studies indicate that rifamycin is a substrate of P-glycoprotein (P-gp) and is expected to inhibit P-gp and breast cancer-resistant protein (BCRP) in the gut. Rifamycin also inhibits renal transporters OAT3, MATE1, and MATE2-K in vitro, but based on observed systemic concentrations of rifamycin after recommended dose administration, clinically significant inhibition of these transporters in vivo is unlikely.
• In vitro cytochrome P450 (CYP) studies show that rifamycin inhibits CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. However, based on observed systemic concentrations of rifamycin after recommended dose administration, clinically relevant inhibition of these enzymes in vivo is unlikely.
• Rifamycin is an inducer of CYP3A4 and CYP2B6 but not CYP1A2 in vitro. Nevertheless, based on observed systemic concentrations of rifamycin after recommended dose administration, clinically significant induction of these enzymes in vivo is unlikely.
• Rifamycin is not metabolized by CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4/5.

The following are the side effects involving Rifamycin:

• Headache
• Constipation
• Abdominal pain
• Fever
• Indigestion

Pregnancy:

Teratogenic Effects - Category A

Data regarding the use of Rifamycin in pregnant women are not available, and therefore, the risks of major birth defects, miscarriage, or adverse outcomes for both the mother and the fetus are unknown. When Rifamycin is taken orally at the recommended dose, the systemic absorption in humans is minimal, indicating that fetal exposure to the drug is not expected. Animal studies conducted with Rifamycin showed no malformations in pregnant rats or rabbits at exposures 25,000 and 500 times higher, respectively than the human exposure achieved with the recommended clinical dose. However, when pregnant rats were treated with Rifamycin at more than 1,000 times the maximum plasma concentration and 25,000 times the systemic exposure during organogenesis, maternal toxicity, decreased fetal weight, and variations in diaphragm formation were observed. Similarly, pregnant rabbits treated with Rifamycin at more than 10 times the maximum human plasma concentration experienced maternal toxicity, decreased fetal weight, and slightly delayed fetal ossifications. It's important to note that all pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. Pregnant women should be informed about the potential risk to the fetus. In animal studies, higher doses of rifamycin did not cause malformations, but they did result in maternal toxicity and fetal developmental effects, while lower doses did not show adverse effects on fetal development in rats and rabbits.

Lactation:

Information regarding the presence of Rifamycin in human milk, its effects on the breastfed infant, or its impact on milk production is currently unavailable. However, based on clinical pharmacology data, the systemic absorption of Rifamycin in humans is minimal after oral administration of the recommended dose. As a result, the exposure of a breastfed infant to Rifamycin through breast milk is expected to be insignificant. Animal lactation data following oral rifamycin administration is not available, but studies in lactating ewes have shown the passage of rifamycin into milk after intravenous injection. When considering the use of Rifamycin, it is important to weigh the developmental and health benefits of breastfeeding against the mother's clinical need for the medication and any potential adverse effects it may have on the breastfed infant, either from Rifamycin itself or the underlying maternal condition.

Pediatric:

The safety and effectiveness of Rifamycin for the treatment of travelers' diarrhea have not been determined in pediatric patients under the age of 18.

Geriatric Use:

Clinical trials conducted with Rifamycin for the treatment of travelers' diarrhea did not involve an adequate number of participants aged 65 and older to establish whether they exhibit different responses compared to younger individuals. However, available clinical experience from other sources has not indicated any notable differences in the treatment outcomes between elderly patients and their younger counterparts.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Rifamycin.

• There is no detailed information regarding the management of an overdose with Rifamycin . If an overdose occurs, it is recommended to discontinue the use of Rifamycin and provide symptomatic treatment. Supportive measures should be initiated as necessary.

Pharmacodynamics:

● Broad-Spectrum Activity of Rifamycin

● Rifamycin exhibits effectiveness against a wide range of pathogens, including both Gram-positive and Gram-negative bacteria, as well as mycobacteria. Notably, it demonstrates remarkable efficacy against E. coli, with a minimum inhibitory concentration (MIC90) of 64-128 mcg/ml, and it does not display cross-resistance with other antimicrobial agents.

● Importance of Specific Indication

● The specific indication for rifamycin is of great significance, particularly due to previous reports highlighting a high risk of generating resistant E. coli strains in patients with inflammatory bowel disease. This emphasizes the need for targeted and appropriate use of rifamycin in clinical practice.

Pharmacokinetic Behavior:

Absorption

After a 250 mg dosage of rifamycin, the reported Cmax (peak concentration), tmax (time to reach Cmax), AUC (area under the concentration-time curve), and mean residence time are 36 mg/L, 5 minutes, 11.84 mg.h/L, and 0.49 hours, respectively.

Volume of Distribution

The volume of distribution of rifamycin, measured after a 250 mg dosage, is reported to be 101.8 L.

Protein Binding

Rifamycin exhibits a protein binding capacity of approximately 80-95%.

Metabolism

Rifamycin is mainly metabolized to a 25-deacetyl metabolite in hepatocytes and intestinal microsomes after absorption.

Route of Elimination

Approximately 18%, 50%, and 21% of the administered dose of rifamycin is recovered in feces within 24, 48, and 72 hours, respectively. Fecal elimination accounts for around 90% of the administered dose, while urinary excretion is negligible.

1. https://www.orpdl.org/durm/meetings/meetingdocs/2019_11_21/drafts/Rifamycin _rifamycin_NDE.pdf
2. https://go.drugbank.com/drugs/DB11753
3. https://reference.medscape.com/drug/Rifamycin -rifamycin-sv-mmx-rifamycin-1000270
4. https://www.rxlist.com/Rifamycin -drug.htm
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf